The subject of the present invention is, in the most general aspect, the prevention and/or treatment of a secondary edema. In particular, the present invention relates to a C1-Inhibitor for use in a method of preventing the formation and/or reducing the size of a secondary edema of the central nervous system (CNS) in a subject wherein the subject has or has had at least one disorder selected from the group consisting of stroke, ischemic stroke, hemorrhagic stroke, perinatal stroke, traumatic brain injury and spinal cord injury. Preferably the secondary edema of the CNS is a secondary brain edema. Another subject of the present invention is the treatment of disorders associated with an increased permeability of the blood brain barrier or the blood spinal cord barrier. And a third subject is a plasma-derived C1-inhibitor for use in a method of preventing, reducing or treating brain ischemia-reperfusion injury.
In this specification, a number of documents are cited. The disclosure content of these documents including manufacturer's manuals is herewith incorporated by reference in its entirety.
The pathology of brain ischemia and the subsequent injury due to reperfusion (brain ischemia-reperfusion injury) is complex and involves a myriad of distinct molecular and cellular pathways. Among these one characteristic of persisting ischemia is structural disintegration of the blood-brain-barrier which in consequence leads to the formation of brain edema. Excessive edema can harm otherwise healthy brain regions simply by mechanic compression and is a frequent cause of worsening of neurological symptoms in stroke patients. Up to now convincing strategies on a pharmacological basis to combat edema formation in acute ischemic stroke are lacking.
Brain edema is defined as an increase in brain volume resulting from a localized or diffuse abnormal accumulation of fluid within the brain parenchyma. In general, brain edema is classified into 4 different groups: vasogenic, cytotoxic, hydrocephalic (or interstitial) and osmotic (or hypostatic) edema. Despite this classification of distinct forms of edema, in most clinical situations there is a combination of different types of edema depending on the time course of the disease. Regarding edema formation subsequent to disturbed cerebral blood flow and cerebral bleeding the cytotoxic and/or vasogenic brain edema seem to play major roles. Moreover, looking at the mediators involved in brain edema formation, many mediators can be mentioned (e.g. Bradykinin), which have many properties other than their effects on brain edema formation (Nag et al. (2009) Acta Neuropathol.; 118:197-217).
Initially in brain edema, the changes in brain volume are compensated by a decrease in cerebrospinal fluid and blood volume, whereby the primary brain edema is mainly a cytotoxic edema. In large hemispheric lesions, progressive swelling exceeds these compensatory mechanisms and an increase in the intracranial pressure (i.e. formation of secondary or malignant brain edema) results in herniations of cerebral tissue leading to death. Hence vasogenic, malignant brain edema continues to be a major cause of mortality after diverse types of brain pathologies such as major cerebral infarcts, hemorrhages, trauma, infections and tumors. The lack of effective treatment for brain edema remains a stimulus for continued interest and research.
Regarding ischemic stroke, secondary brain edema is a frequent cause of secondary infarct growth and subsequent deterioration of neurological symptoms during the course of ischemic stroke (Ayata and Ropper (2002) J Clin Neurosci.; 9:113-124; Bardutzky and Schwab (2007) Stroke; 38:3084-3094). In ischemic stroke malignant middle cerebral artery (MCA) infarction is a term used to describe complete MCA territory infarction with significant space occupying effect and herniation of brain tissue. The incidence of malignant MCA infarction is estimated to be less than 1% of all strokes. The mortality with conservative forms of medical treatment is approximately 80% and coma terminates in brain death within 2-5 days of onset. Death usually occurs from progressive swelling of the ischemic brain tissue, brain tissue shifts, focal increase in intracranial pressure, and the extension of ischemia to adjacent vascular territories. Survivors of this kind of stroke are disabled with poor quality of life. So far no medication has proven to persistently reduce brain edema in cerebral ischemia and often the last treatment approach as life saving procedure is the decompressive hemicraniectomy. Furthermore, molecular mechanisms underlying edema formation and successive neuronal degeneration in ischemic stroke are largely unknown.
The kallikrein-kinin system (KKS) is initiated by blood coagulation factor XII (FXII, Hageman factor) and plays an important role in the regulation of vascular permeability and edema formation (Leeb-Lundberg et al. (2005) Pharmacol. Rev.; 571:27-77). The activation of the KKS was recently proven also in stroke patients (Wagner et al. (2002) J. Neurol. Sci.; 202:75-76). Kinins (e.g. bradykinin, kallidin) constitute the end products of the KKS. Kinins are highly active proinflammatory peptide hormones which are released by kallikreins from their precursors, kininogens, during various kinds of tissue injury including brain ischemia. The cellular effects of kinins are mediated by two different bradykinin receptors, B1R and B2R. Activation of these receptors triggers inflammatory processes in the target organ such as the release of proinflammatory cytokines or the attraction of immune cells as well as increased vascular permeability.
Recently, blockade of B1R, but not B2R, reduced blood-brain-barrier damage and edema formation in experimental models of focal cerebral ischemia (Austinat et al. (2009) Stroke; 40:285-293) and traumatic brain injury (Raslan et al. (2010) J. Cereb. Blood Flow Metab.; 30:1477-1486) in mice suggesting functional relevance of KKS on brain edema formation in the acute phase of ischemic stroke and traumatic brain injury.
In studies preventing the activation of KKS via inhibition of FXII, which is activated physiologically upon contact with negatively charged surfaces (contact activation), neuropathological outcome following acute experimental stroke (Hagedorn et al. (2010) Circulation; 121:1510-1517; Kleinschnitz et al. (2006) JEM; 203(3):513). was investigated.
C1-esterase inhibitor (C1-INH) is a 478 amino acid glycoprotein belonging to the superfamily of serine protease inhibitors called serpins. Its designation originates from the initial description as the only known physiological inhibitor of the classical complement pathway in blood and tissue. However, C1-INH is also a major regulator of the KKS by blocking activated FXII and plasma kallikrein. Apart from several other functions (e.g. FXIa inhibition), it is the only known physiological inhibitor of C1s and C1r, the activated homologous serin proteases of the first component of the complement system.
Previous studies have demonstrated a beneficial role of C1-INH formulations in animal models of ischemic stroke itself (De Simoni et al. (2004) Am. J. Pathol.; 164:1857-1863; Gesuete et al. (2009) Ann. Neurol.; 66:332-342) as well as of traumatic brain injury (Longhi et al. (2009) Crit. Care Med.; 37:659-665) and traumatic spinal cord injury (Tei et al. (2008) Neurol. Res.; 30:761-767) but the underlying molecular mechanisms are largely unknown. Furthermore, these studies were focussing on acute neuropathological outcomes whereas effects on (secondary) brain edema, i.e. preventing its formation and/or reducing its size, were not disclosed. In addition, de Simoni et al. (2004; Am. J. Pathol.; 164:1857-1863) disclose that plasma-derived C1-inhibitor (15 U/mouse) was just effective in the murine model of ischemia/reperfusion injury when given at the start of reperfusion, whilst efficacy was completely lost when given 30 minutes after start of reperfusion.
Hence, it is apparent that there still exists a need for a medication for the treatment or prophylaxis of a secondary brain edema occurring after an occlusion of a blood vessel in the brain. Therefore, it is an object of the present invention to satisfy such a need.